Eungu Kang

Pathogenic SCN1A variants in pore-associated regions (P-loop/selectivity filter) tend to be more destabilizing—compatible with, though not proof of, a candidate proteostasis-impaired mechanism complementary to gating dysfunction. Pathogenic variants in S4 voltage-sensing domains are predominantly stability-neutral, a pattern compatible with—but not direct evidence of—gating dysfunction.

Abstract FBXO11 binds SKP1 within an SCF E3 ubiquitin ligase complex, where it recognizes substrates for ubiquitination and degradation. Pathogenic FBXO11 variants cause neurodevelopmental disorders, yet several retain normal SKP1 binding, indicating that disrupted SKP1 binding alone cannot account for disease. We integrated multi-conformational AlphaFold3 models with FoldX and Rosetta stability predictions to evaluate 44 missense variants (23 pathogenic, 21 benign).